The present invention is a method for preparing multiwall polymer microspheres, particularly for use in controlled delivery systems.
This is a continuation-in-part of U.S. Ser. No. 07/906,403, filed Jul. 1, 1992, by Edith Mathiowitz and Robert Langer, which is a continuation-in-part of U.S. Ser. No. 07/045,840-entitled xe2x80x9cPreparation of Multiwall Polymeric Microcapsulesxe2x80x9d filed May 1, 1987 by Edith Mathiowitz and Robert S. Langer, issued as U.S. Pat. No. 4,861,627 on Aug. 29, 1989.
Controlled delivery of substances, for example, drugs, insecticides, fertilizers, detergents, perfumes, and indicators, can be accomplished using a variety of processes. In one type of delivery system, a polymeric capsule is formed around or incorporating the substance to be delivered. The form and composition of the polymer or polymers determines the method that can be used to incorporate the substance, the environment in which the capsule can be used, and the type of substance which can be incorporated.
One process for preparing microspheres is a hot-melt technique. The melted polymer is mixed with the drug, and the mixture is suspended in a non-solvent where it is cooled and solidified. A major disadvantage of this process is that only low melting polymers can be used with thermolabile substances.
The solvent evaporation technique, disclosed, for example, by U.S. Pat. No. 3,523,906 to M. N. Vrancken and U.S. Pat. No. 3,960,757 to M. Morishita, has been used to prepare microspheres from biodegradable polymers, as reported in the literature and by H. Jaffe in U.S. Pat. No. 4,272,398. The procedure generally consists of dissolving a polymer in methylene chloride or other volatile solvents, dissolving or suspending a drug in the solution and emulsifying the resulting mixture in an aqueous phase containing an emulsifier. The solvent is evaporated to produce microspheres containing the substance to be incorporated. The technique of Morishita dissolves a hydrophobic polymer in an organic solvent which is poorly miscible with water and has a boiling point less than water. A substance is dissolved or mixed in the polymer solution, the solution is emulsified in an aqueous solution of a hydrophilic colloid or surface active agent, and the organic solvent is removed by evaporation. A major limitation of this method is that the solvents used can be harmful to biologically active material to be encapsulated.
Yet another method used to form microcapsules is phase separation. Essentially, a polymer is forced to precipitate around a core by addition of non-solvent or by addition of a second polymer which is incompatible with the first polymer.
A polymer coating can be added to spherical particles using a fluidized bed method. In this method, microspheres of one polymer or particles of the substance to be encapsulated are suspended in a vertical column by air flow. The polymer used for coating is dissolved in an appropriate solvent and sprayed down over the suspended particles. A uniform polymer coating may be obtained for particles larger than 50 xcexcm. This method, however, is not appropriate for water-soluble polymers due to the time required for water evaporation.
U.S. Pat. No. 4,861,627 to Mathiowitz, describes a method for making polymeric microspheres with a polymeric core made of a first polymer, a uniform coating layer made of a second polymer, and a substance incorporated in at least one of the polymers. The first and second polymer are immiscible in each other, and separate into distinct phases when dissolved in appropriate solvents or when melted together. The interfacial tension of the polymers causes one polymer to engulf the other polymer, resulting in microspheres with a core of one polymer, and a uniform coating of the second polymer. The microspheres are made from polymers that are soluble in a volatile organic solvent.
While all of these methods are useful in making microspheres or microcapsules for controlled delivery, they have certain disadvantages. The coating method described in U.S. Pat. No. 4,861,627 provides microspheres with uniform layers, but is not applicable to hydrophilic polymers that are not soluble in volatile organic solvents. Other coating methods, which are applicable to hydrophilic polymers, do not always yield uniform polymer layers. The best one can do at present is to dip microspheres formed of one polymer into a bath of a second polymer (pan coating). However, the coatings tend to be non-uniform both with respect to coverage and to thickness. This can be fatal to a system for controlled delivery, as in controlled drug delivery systems requiring linear release of the drug as the polymer degrades in vivo. Further, many of these methods require multiple steps, with increasing quality control problems at each stage. The final yield is frequently low.
It is therefore an object of the present invention to provide a one step method for manufacturing delivery systems consisting of two or more hydrophilic polymers in microcapsule form.
It is another object of the present invention to provide a method for making polymeric delivery devices where substances, in particle form if solids, or live cells, can be incorporated directly into polymers and which can be conducted at relatively low temperatures to avoid damaging any thermolabile substances to be incorporated.
A single step method for preparing multilayer polymeric drug, protein, or cell delivery devices from two or more hydrophilic polymers is disclosed. Any two or more different biodegradable, or non-degradable, water soluble polymers which are not soluble in each other at a particular concentration as dictated by their phase diagrams may be used. The multilayer microcapsules produced by the method have uniformly dimensioned layers of polymer and can incorporate a range of substances including biologically active agents such as drugs or cells, or diagnostic agents such as dyes.
In the preferred embodiment, two hydrophilic polymers are dissolved in an aqueous solution, a substance to be incorporated is dispersed or dissolved in the polymer solution, the mixture is suspended in a continuous phase, and the solvent is slowly evaporated, creating microspheres with an inner core formed by one polymer and an outer layer of the second polymer. The continuous phase can be either an organic oil, a volatile organic solvent, or an aqueous solution containing a third polymer that is not soluble with the first mixture of polymers and which will cause phase separation of the first two polymers as the mixture is stirred.
In another embodiment, two or more hydrophilic polymers are dissolved in mixtures of organic and aqueous solutions and then mixed together. By selecting the appropriate solvents and polymers, the two solutions will not be soluble in each other and will result in a suspension or emulsion. This insoluble mixture can then be suspended in yet another continuous phase, in which neither polymer is soluble, and the solvents are removed by evaporation.
In another embodiment, two hydrophilic polymers that gel upon a change in temperature are separately dissolved to form two polymer solutions. These solutions are mixed and phase separated so that one layer engulfs the other, then the temperature is altered to gel one of the polymers. Optionally, the temperature can be altered to gel the second polymer. In some embodiments, there is no need to dry the resulting microspheres, particularly when cells are encapsulated.
In another embodiment, polymers are selected that can be ionically or covalently cross-linked, or cross-linked by heating. Two polymer solutions are mixed and phase separated so that one polymer engulfs the other, then one or both of the polymers are cross-linked by adding a cross linking agent, for example, ions to effect ionic crosslinking, glutaraldehyde to effect chemical crosslinking with functional groups such as amine groups, or free-radical initiation effected by azo-bisisobutyronitrile (AIBN) or t-butyl peroxide, by photoinitiators active in the ultraviolet (UV) region, such as benzoin ethyl ether, or photoinitiators active in visible light to crosslink free-radical polymerizable groups, such as carbon-carbon double bonds.
In a further embodiment, solvents in polymer solutions are evaporated rapidly to produce multiple spheres of a first hydrophilic polymer within a layer of a second hydrophilic polymer. The rate of evaporation can be varied to form a core of the first polymer and a coating of the second polymer, or multiple spheres of a first polymer within a layer of the second polymer.
Important parameters for producing multi-layered microcapsules of the desired composition are: the selection of the hydrophilic polymers, including the purity and the molecular weights of the polymers, the solvent, the solubility and concentration of the polymers in the solvent, the selection and composition of the non-solvent, including adding an emulsifier to the non-solvent, the processing temperature, the rate of solvent evaporation, the rate of mixing, the physical and chemical properties of the substance to be incorporated, and ionic composition of the solvent (i.e., salt concentration). The optimum conditions can be determined empirically by one skilled in the art by measuring the surface tension or interfacial tension of the polymers under the processing conditions.
Examples demonstrate the production of multilayered microcapsules composed of polyethylene glycol and dextran, and gelatin and agarose.